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Anti-Epileptogenic Agents in Traumatic Brain Injury

IP.com Disclosure Number: IPCOM000004834D
Publication Date: 2001-Jun-28
Document File: 2 page(s) / 27K

Publishing Venue

The IP.com Prior Art Database

Related People

Marcus Brady: CONTACT

Related Documents

09/041,371: PATAPP

Abstract

1. Develop dual action anticonvulsant/anti-epileptogenic compounds for the prevention of post-traumatic epilepsy 2. Prove efficacy in vitro and in vivo in models of epilepsy and epileptogenesis 3. Develop an in vivo animal model of traumatic brain injury

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Title:

Anti-Epileptogenic Agents in Traumatic Brain Injury

Authors:

Names, credentials, and organization affiliation only.

1. Donald Weaver, Ph.D. Chemistry, M.D. Neurology, Epilepsy Project Leader, Queen's University

2. Angela Lyon, M.Sc., Epilepsy Project Coordinator, Queen's University

3. Maura Campbell, Ph.D., Epilepsy Project Manager, Neurochem Inc.

4. Francine Gervais, Ph.D., Vice President Research and Development, Neurochem Inc.

Objectives (2-3):

1. Develop dual action anticonvulsant/anti-epileptogenic compounds for the prevention of post-traumatic epilepsy

2. Prove efficacy in vitro and in vivo in models of epilepsy and epileptogenesis

3. Develop an in vivo animal model of traumatic brain injury

Description Methodology Conclusion:

An outline of up to 250 words describing research conducted or the rehabilitation model or service being presented, must be typed in the space below.

Development of compounds having dual activity with anti-convulsant and anti-epileptogenic properties was undertaken based on rational drug design principles. Compounds with such activities would prevent the genesis and the progression of epilepsy. Over 270 compounds were synthesized and tested for anti-convulsant and anti-epileptogenic activity using a comprehensive series of in vitro and in vivo models of seizure and epileptogenesis. From this testing two lead candidates were identified: an anti-epileptogenic compound and an anti-convulsant pro-drug which following metabolism is converted to an anti-epileptogenic compound.

The activity profile of both compounds suggests strong anti-epileptogenic/convulsant activity. These compounds were found to:

increase inhibition of neuronal excitation by upregulating GABAergic function;

increase inhibition of neuronal excitation by downregulating glutamatergic function, by binding the glycine site on the NMDA receptor;

act as anticonvulsants in vivo preventing seizures induced by Maximal ElectroShock, Pentylenetetrazol and Pilocarpine;

act as anti-epileptogenics in vivo preventing seizures in the Spontaneous Recurrent Seizure and Kindling models of epileptogenesis;

cross the Blood Brain Barrier in vivo with minimal neurotoxicity.

These dual action compounds would be beneficial not only to epilepsy patients but also to Traumatic Brain Injury (TBI) patients. These compounds could be administered to all TBI patients as a neuroprotective agent to prevent the development of post-traumatic epilepsy. A Brain Trauma Animal Model has been developed to mimic the human situation by provoking a subdural haematoma. This Brain Trauma model will be used for validating and confirming neuroprotective and anti-epileptogenic activity of these lead molecules.

This work is done in collaboration with Neurochem and Dr. D. F. Weaver's laboratory at Queen's University (Canada).